This project will focus on two areas of extra-striatal pathology in HD (cortex and amygdala) and their relationship to possible pathogenetic mechanisms and to non-motor clinical features (dementia, depression, apathy and irritability). Our preliminary cell counting data suggests that neuronal loss occurs in layers III and V and especially in layer VI. We propose to quantify neuronal depletion using computer-assisted neuronal cell counting methods. The regional topography of changes in relation to the corticostriatal and striato-pallido-thalamo-cortical connections may allow inferences about the pathogenesis of cortical neuropathology. In addition, we will correlate the extent of pathology in four cortical regions with nonmotor clinical symptoms. We will better define the neurotransmitter specificity of the cortical pathology using in situ hybridization, receptor autoradiography, and immunocytochemistry. Our second aim is to investigate pathology in the amygdala and associated nuclei, regions where pathologic changes may result in psychiatric abnormalities. Neurotransmitter-specific studies, including our preliminary data on opiate receptors, have suggested that these regions are affected. We will count neurons, using methods similar to the cortical studies; study the details of neurotransmitter-related lesions using in situ hybridization, immunocytochemistry, and receptor autoradiography; and correlate the results with clinical symptoms. Taken together, these studies should further our knowledge of the pathogenetic mechanisms of HD and the relationship between neuropathology and clinical symptoms.